Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids (Retracted article. See vol. 323, 2022)
Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids (Retracted article. See vol. 323, 2022)
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DOI：
10.1152/ajpendo.00202.2013
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发表时间：
2014-01-01
影响因子：
5.1
通讯作者：
Xie, Zhonglin
中科院分区：
文献类型：
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作者：
Li, Hongliang;Lee, Jiyeon;Xie, Zhonglin
营养过剩与肥胖、胰岛素抵抗和2型糖尿病的发生有关。然而，在营养过剩的情况下发生胰岛素抵抗的潜在机制还不完全清楚。我们研究了AMP激活蛋白激酶（AMPK）的激活是否可以预防由高蛋白饮食（HPD）和过量氨基酸引起的肝脏胰岛素抵抗。HepG 2细胞暴露于过量氨基酸会降低AMPK磷酸化，上调Notch 1表达，并损害胰岛素刺激的Akt Ser（473）和胰岛素受体底物-1（IRS-1）Tyr（612）磷酸化。Notch 1的抑制防止氨基酸诱导的胰岛素抵抗，这是伴随着Rbp-Jk，分裂的毛和增强子-1，和叉头盒O 1的表达减少。从机制上讲，mTORC 1信号被过量的氨基酸激活，然后通过激活信号转导和转录激活因子3（STAT 3）正向调节Notch 1的表达。二甲双胍激活AMPK可抑制mTORC 1-STAT 3信号传导，从而防止过量氨基酸损伤胰岛素信号传导。最后，HPD喂养抑制AMPK活性，激活mTORC 1/STAT 3/Notch 1信号传导，并诱导胰岛素抵抗。长期给予二甲双胍或雷帕霉素可抑制HPD激活的mTORC 1/STAT 3/Notch 1信号通路并预防肝脏胰岛素抵抗。我们的结论是，上调Notch 1表达的过度活跃mTORC 1信号是一个重要的事件，在肝脏胰岛素抵抗的发展中存在的过量氨基酸。AMPK的激活通过抑制mTORC 1/STAT 3/Notch 1信号通路防止氨基酸诱导的胰岛素抵抗。
Nutrient overload is associated with the development of obesity, insulin resistance, and type 2 diabetes. However, the underlying mechanisms for developing insulin resistance in the presence of excess nutrients are incompletely understood. We investigated whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic insulin resistance that is induced by the consumption of a high-protein diet (HPD) and the presence of excess amino acids. Exposure of HepG2 cells to excess amino acids reduced AMPK phosphorylation, upregulated Notch1 expression, and impaired the insulin-stimulated phosphorylation of Akt Ser(473) and insulin receptor substrate-1 (IRS-1) Tyr(612). Inhibition of Notch1 prevented amino acid-induced insulin resistance, which was accompanied by reduced expression of Rbp-Jk, hairy and enhancer of split-1, and forkhead box O1. Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). Activation of AMPK by metformin inhibited mTORC1-STAT3 signaling, thereby preventing excess amino acid-impaired insulin signaling. Finally, HPD feeding suppressed AMPK activity, activated mTORC1/STAT3/Notch1 signaling, and induced insulin resistance. Chronic administration of either metformin or rapamycin inhibited the HPD-activated mTORC1/STAT3/Notch1 signaling pathway and prevented hepatic insulin resistance. We conclude that the upregulation of Notch1 expression by hyperactive mTORC1 signaling is an essential event in the development of hepatic insulin resistance in the presence of excess amino acids. Activation of AMPK prevents amino acid-induced insulin resistance through the suppression of the mTORC1/STAT3/Notch1 signaling pathway.